The U.S. Food and Drug Administration (FDA) has approved sildenafil citrate tablets for the treatment of pulmonary arterial hypertension (WHO Group I) under the brand name REVATIO®. The recommended dose of REVATIO® is 20 mg three times a day.
Sildenafil citrate was first approved by the FDA for the treatment of male erectile dysfunction under the brand name VIAGRA®.
Sildenafil is reported to be a selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5 (PDE5). Its effects in treating pulmonary arterial hypertension (and erectile dysfunction) occur by enhancing the downstream effects of nitric oxide (NO) mediated vasorelaxation. PDE5 is found in pulmonary vascular smooth muscle and the corpus cavernosum, as well as in tissues such as vascular and visceral smooth muscle and in platelets. Sildenafil increases cyclic-GMP (cGMP) by inhibiting PDE5. PDE5 is responsible for degradation of cGMP. As a result, sildenafil increases cGMP within pulmonary vascular smooth muscle cells. In patients with pulmonary hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilation in the systemic circulation (see, e.g., REVATIO® product literature).
In addition to its therapeutic benefits in diseases such as pulmonary arterial hypertension (PAH) and erectile dysfunction, sildenafil is reported to be efficacious in the treatment of sexual dysfunctions associated with SSRI administration. See, e.g., Stimmel, G L, “Sexual dysfunction and psychotropic medications” CNS Spectr. (2006) 11:8(Suppl 9):24-30 and Wang, W-F et al. “Selective serotonin reuptake inhibitors in the treatment of premature ejaculation” Chin Med J (2007) 120(11):1000-1006. Sexual dysfunctions are a main side effect of SSRIs, and include difficulties with libido, arousal, delayed or absent orgasm (e.g., anorgasmia in women), and delayed ejaculation, anejaculation, or erectile dysfunction in men. Ibid. In patients suffering from sexual dysfunction as a result of SSRI treatment, administration of sildenafil as adjunct therapy may improve and sustain arousal, for example, in the patient by increasing blood flow, and sildenafil is thought to exert an indirect beneficial effect on other aspects of sexual response via the same mechanism. See, e.g., Stimmel, G L. CNS Spectr. (2006) 11:8(Suppl 9):24-30.
Sildenafil has been proposed as a possible therapeutic in the treatment of a number of other conditions as well. These include female sexual dysfunction, including sexual dysfunction associated with menopause, such as difficulties with sexual arousal. See, e.g., Mattar, C N et al. “Care of women in menopause: sexual function, dysfunction and therapeutic modalities” Ann Acad Med Singapore (2008) 37:215-223. Other conditions for which sildenafil may provide a therapeutic benefit include high-altitude illness (see, e.g., Luks, A M et al CHEST (2008) 133:744-755), pain, stroke, multiple sclerosis, and irritable bowl syndrome (see, e.g., Sharma, R Indian J Med Sci (2007) 61:667-679 and Uthayathas, S et al. Pharmacological Reports (2007) 59:150-163).
Despite its effectiveness in treating diseases such as PAH and erectile dysfunction, the administration of solid oral sildenafil dosage forms may also cause undesirable side effects. At high dosages, the incidence of such side effects increase, for example, abnormal vision problems (ranging from blue or green halo effects to blurring), dyspepsia, nasal congestion, blinding headaches, flushing, redness, diarrhea, dizziness, rash, and urinary tract infection. Other more serious side effects may occur in some cases resulting from a physiological predisposition, adverse drug interaction or potentiation, or by drug abuse. Such side effects include syncope (loss of consciousness), priapism (erection lasting 4 hours or more), and increased cardiac risk (coital coronaries). In particular, hypotension crisis may result from the combination of sildenafil citrate and organic nitrates, causing death in some cases. Hence, its administration to patients who are concurrently using organic nitrates (such as nitroglycerin) in any form is contraindicated. Moreover, the long-term effects of large doses of sildenafil-containing drugs are unknown (Handy B., “The Viagra® Craze,” Time, pp. 50-57 (May 4, 1998)).
Many drugs exhibit low bioavailabilities owing to extensive first pass metabolism. Differences in bioavailability may have profound clinical significance. Sildenafil citrate, for example, exhibits only a 40% bioavailability after oral administration via tablet form, of which the active metabolite accounts for about one-half.
Compared to the administration of solid oral dosage forms absorbed in the gastrointestinal tract, the oral cavity presents the possibility for more rapid and efficient drug delivery because of its rich vascular supply. The oral cavity exhibits a minimal barrier to drug transport and may result in a rapid rise in serum concentration of drug.
However, the formulation of dosage forms for administration to the oral mucosa often poses non-trivial problems. For significant drug absorption to occur across the oral mucosa, the drug must have a prolonged exposure to the mucosal surface and the formulation must be both chemically stable and pharmaceutically acceptable to patients.
WO 01/35926 discloses sildenafil dosage forms for non-oral use, such as nasal delivery. However, there is currently no commercially available dosage form for oral spray delivery of sildenafil.
Thus, there is an ongoing need and desire for discreet and convenient sildenafil dosage forms for the treatment of diseases such as pulmonary arterial hypertension and SSRI-induced sexual dysfunction, which are both chemically stable and pharmaceutically acceptable.